You play engineer Isaac Clarke who is part of a team sent to repair the USG Ishimura, a mining vessel that went out of contact shortly after uncovering an alien artifact. Upon arrival, you discover that the crew has been massacred and reanimated as horrific monsters who kill most of your team and cut you off from your ship. You must fight your way through these necromorphs and the hazards of the damaged spaceship to find a way to escape with your life.

Isaac is equipped with a space suit and some mining tools that serve as makeshift weapons, all of which may be upgraded as the game progresses.

The space setting provides some unique challenges including lack of oxygen and zero gravity combat in some areas. Your space suit provides you with oxygen tanks and gravity boots to help you deal with these, as well as giving you the abilities of stasis, allowing you to temporarily slow down machines and adversaries, and kinesis, allowing you to attract and repel objects remotely.